The HIV epidemic in the United States has affected at least two generations of gay men. Despite numerous efforts to intervene on this public health crisis, HIV infections continue to escalate, especially among young men. This condition is compounded by an ever-growing number of gay men who are aging and living with HIV. We must enact an innovative and proactive vision and framework for HIV prevention that moves us beyond the undertakings rooted in social-cognitive paradigms that have informed this work for the past 25 years. A new framework for HIV prevention must give voice to gay men; must consider the totality of their lives; must delineate the underlying logic, which directs their relation to sex and HIV; and must concurrently respect their diverse life experiences. This approach should be rooted in a biopsychosocial paradigm, should be informed by both theory and practice, and should be directed by three theoretical lenses--a theory of syndemics, developmental theories, and contextual understandings of HIV disease. Taken together, these elements are a call to action for research and practice psychologists who are working to improve the lives of gay men.